Myocyte remodeling due to fibro-fatty infiltrations influences arrhythmogenicity

The onset of cardiac arrhythmias depends on the electrophysiological and structural properties of cardiac tissue. Electrophysiological remodeling of myocytes due to the presence of adipocytes constitutes a possibly important pathway in the pathogenesis of atrial fibrillation. In this paper we perform an in-silico study of the effect of such myocyte remodeling on the onset of atrial arrhythmias and study the dynamics of arrhythmia sources-spiral waves. We use the Courtemanche model for atrial myocytes and modify their electrophysiological properties based on published cellular electrophysiological measurements in myocytes co-cultered with adipocytes (a 69-87 % increase in APD90 and an increase of the RMP by 2.5-5.5 mV). In a generic 2D setup we show that adipose tissue remodeling substantially affects the spiral wave dynamics resulting in complex arrhythmia and such arrhythmia can be initiated under high frequency pacing if the size of the remodeled tissue is sufficiently large. These results are confirmed in simulations with an anatomically accurate model of the human atria

Arrhythmogenicity of fibro-fatty infiltrations

The onset of cardiac arrhythmias depends on electrophysiological and structural properties of cardiac tissue. One of the most important changes leading to arrhythmias is characterised by the presence of a large number of non-excitable cells in the heart, of which the most well-known example is fibrosis. Recently, adipose tissue was put forward as another similar factor contributing to cardiac arrhythmias. Adipocytes infiltrate into cardiac tissue and produce in-excitable obstacles that interfere with myocardial conduction. However, adipose infiltrates have a different spatial texture than fibrosis. Over the course of time, adipose tissue also remodels into fibrotic tissue. In this paper we investigate the arrhythmogenic mechanisms resulting from the presence of adipose tissue in the heart using computer modelling. We use the TP06 model for human ventricular cells and study how the size and percentage of adipose infiltrates affects basic properties of wave propagation and the onset of arrhythmias under high frequency pacing in a 2D model for cardiac tissue. We show that although presence of adipose infiltrates can result in the onset of cardiac arrhythmias, its impact is less than that of fibrosis. We quantify this process and discuss how the remodelling of adipose infiltrates affects arrhythmia onset

Myocyte Remodeling Due to Fibro-Fatty Infiltrations Influences Arrhythmogenicity

The onset of cardiac arrhythmias depends on the electrophysiological and structural properties of cardiac tissue. Electrophysiological remodeling of myocytes due to the presence of adipocytes constitutes a possibly important pathway in the pathogenesis of atrial fibrillation. In this paper we perform an in-silico study of the effect of such myocyte remodeling on the onset of atrial arrhythmias and study the dynamics of arrhythmia sources—spiral waves. We use the Courtemanche model for atrial myocytes and modify their electrophysiological properties based on published cellular electrophysiological measurements in myocytes co-cultered with adipocytes (a 69–87 % increase in APD90 and an increase of the RMP by 2.5–5.5 mV). In a generic 2D setup we show that adipose tissue remodeling substantially affects the spiral wave dynamics resulting in complex arrhythmia and such arrhythmia can be initiated under high frequency pacing if the size of the remodeled tissue is sufficiently large. These results are confirmed in simulations with an anatomically accurate model of the human atria

Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate between normal rhythm and arrhythmia based on frequency-dependent gating and ii) generate an ionic current for termination of the detected arrhythmia. We show in silico, that for both human atrial and ventricular arrhythmias, activation of these channels leads to rapid and repeated restoration of normal excitation rhythm. Experimental validation is provided by injecting the designed channel current for arrhythmia termination in human atrial myocytes using dynamic clamp

Long-read sequencing to unravel complex structural variants of CEP78 leading to cone-rod dystrophy and hearing loss

Inactivating variants as well as a missense variant in the centrosomal CEP78 gene have been identified in autosomal recessive cone-rod dystrophy with hearing loss (CRDHL), a rare syndromic inherited retinal disease distinct from Usher syndrome. Apart from this, a complex structural variant (SV) implicating CEP78 has been reported in CRDHL. Here we aimed to expand the genetic architecture of typical CRDHL by the identification of complex SVs of the CEP78 region and characterization of their underlying mechanisms. Approaches used for the identification of the SVs are shallow whole-genome sequencing (sWGS) combined with quantitative polymerase chain reaction (PCR) and long-range PCR, or ExomeDepth analysis on whole-exome sequencing (WES) data. Targeted or whole-genome nanopore long-read sequencing (LRS) was used to delineate breakpoint junctions at the nucleotide level. For all SVs cases, the effect of the SVs on CEP78 expression was assessed using quantitative PCR on patient-derived RNA. Apart from two novel canonical CEP78 splice variants and a frameshifting single-nucleotide variant (SNV), two SVs affecting CEP78 were identified in three unrelated individuals with CRDHL: a heterozygous total gene deletion of 235 kb and a partial gene deletion of 15 kb in a heterozygous and homozygous state, respectively. Assessment of the molecular consequences of the SVs on patient’s materials displayed a loss-of-function effect. Delineation and characterization of the 15-kb deletion using targeted LRS revealed the previously described complex CEP78 SV, suggestive of a recurrent genomic rearrangement. A founder haplotype was demonstrated for the latter SV in cases of Belgian and British origin, respectively. The novel 235-kb deletion was delineated using whole-genome LRS. Breakpoint analysis showed microhomology and pointed to a replication-based underlying mechanism. Moreover, data mining of bulk and single-cell human and mouse transcriptional datasets, together with CEP78 immunostaining on human retina, linked the CEP78 expression domain with its phenotypic manifestations. Overall, this study supports that the CEP78 locus is prone to distinct SVs and that SV analysis should be considered in a genetic workup of CRDHL. Finally, it demonstrated the power of sWGS and both targeted and whole-genome LRS in identifying and characterizing complex SVs in patients with ocular diseases

Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and